Isolated pulmonary metastases define a favorable subgroup in metastatic pancreatic cancer

Abstract

Purpose

Liver metastasis represents the first site of dissemination in >80% of metastatic pancreatic cancer (PC) patients. Pulmonary metastasis as first site of dissemination in PC is a rare event and might define a biologically distinct subgroup in metastatic PC.

Methods

Consecutive PC patients who were diagnosed or treated with isolated pulmonary metastases at our high-volume comprehensive cancer center were included in a prospectively maintained database between 2002 and 2015. Medical records and correlating computed tomography findings (CT) were retrospectively analyzed.

Results

A total of 40 PC patients with isolated pulmonary metastases were identified. Pulmonary metastases represented disease recurrence after initial resection of PC in 22 patients and disease progression of locally advanced pancreatic cancer in 5 patients. 14 out of 27 PC patients (56%) had received chemoradiotherapy for localized disease prior to pulmonary metastasis. Data on 1st-line treatment for pulmonary metastases was available for 38 patients: most patients (71%) received a gemcitabine-based chemotherapy regimen, 5 patients (13%) received best supportive care. After a median follow-up of 37.3 months, median survival after diagnosis of pulmonary metastasis was estimated with 25.5 months (95% CI 19.1–31.8); a significantly improved survival after diagnosis of pulmonary metastasis was observed for patients with less than 10 lung metastases (31.3 vs 18.7 months, p = 0.003) and for an unilateral localization of lung involvement (31.3 vs 21.8 months, p = 0.03).

Conclusions

Our results suggest a favorable outcome of PC patients with isolated pulmonary metastases. Further research is warranted to elucidate the specific molecular characteristics of this rare subgroup.

Introduction

Despite a declining overall cancer mortality, pancreatic cancer (PC) related mortality has been on the rise in recent years, ranking fourth and fifth in terms of organ specific cancer mortality in the US and Europe respectively [1], [2]. A further increase in incidence is predicted to make PC the second leading cause of cancer related mortality by 2030 [3]. At initial diagnosis of PC, approximately 80% of patients present with advanced disease [4]. Notwithstanding decades of research aiming on improving the dire prognosis of advanced PC, five-year survival rate remains low at around 5–10% [1].

A significant improvement in overall survival has been achieved for advanced PC patients with good performance status, using the intensive chemotherapy regimens 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or by adding nab-paclitaxel to standard-of-care gemcitabine [5], [6]. Erlotinib, the only FDA and EMA approved targeted agent for advanced PC, provides only a modest clinical benefit in an unselected metastatic PC population [7]. Many other targeted treatment approaches that have substantially improved the prognosis in a variety of solid malignancies have similarly failed to provide a significant benefit for PC patients [8], [9]. Recent advances in genomic sequencing have improved the understanding of cancer initiation and progression of PC. PC is driven by mutations in a small subset of genes that are almost ubiquitously mutated in PC patients (KRAS, TP53, SMAD4, CDKN2A) [10]. Mutations in other genes – particularly druggable mutations – occur at a low frequency making PC a genetically heterogeneous disease [10]. This provides a likely explanation why unselected targeted treatment approaches in PC have been doomed to fail so far. Identification of genetically and clinically unique PC subgroups thus might pave the way for successful targeted treatment approaches.

Dissemination is a late step during the evolution of PC – occurring approximately seven years after primary tumor formation [11]. Genetic alterations present in metastatic lesions reflect the mutational landscape in the founder clone and might determine metastatic pattern of PC [11]. Metastatic pattern of PC could therefore indicate distinct clinical and genetic subgroups. A majority of patients with disseminated PC present with liver metastases. Pulmonary metastases as first site of dissemination are a rare event [11], [12]. We hypothesized that patients with isolated pulmonary metastases might define a clinically distinct subgroup of PC and sought to determine outcome and prognostic factors of these patients.